Time course of apoptotic tumor response after a single dose of chemotherapy: Comparison with 99mTc-annexin V uptake and histologic findings in an experimental model

Toshiki Takei, Yuji Kuge, Songji Zhao, Masayuki Sato, H. William Strauss, Francis G. Blankenberg, Jonathan F. Tait, Nagara Tamaki

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33 Scopus citations

Abstract

In tumors the process of apoptosis occurs over an interval of time after chemotherapy. To determine the best timing for detecting apoptosis in vivo with 99mTc-annexin V after chemotherapy, we examined the changes in 99mTc-annexin V accumulation over time in comparison with those of caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) expression level after cyclophosphamide treatment in an experimental model. Methods: Hydrazinonicotinamide (HYNIC)-annexin V was labeled with 99mTc (99mTc-annexin V). Rats were inoculated with allogenic hepatoma cells (KDH-8) into the left calf muscle. Eleven days after the inoculation, the rats were randomly divided into the group receiving a single dose of cyclophosphamide (150 mg/kg intraperitoneally) and the control group. 99mTc-Annexin V (18.5 MBq [0.5 mCi] per rat) was injected intravenously in the rats 4, 12, and 20 h after the treatment and also to the control rats (n = 5 in each group). Radioactivity in tissues was determined 6 h after 99mTc-annexin V injection. Immunostaining of caspase-3 and TUNEL were performed to detect apoptosis, and the rates of positively stained cells were calculated. Results: 99mTc-Annexin V accumulation in tumors significantly increased at 20 h (0.077 ± 0.007 [%ID/g] x kg, where %ID/g = percentage injected dose per gram) but not at 4 or 12 h (0.048 ± 0.008 and 0.052 ± 0.014 [%ID/g] x kg, respectively) after cyclophosphamide treatment. 99mTc-Annexin V accumulation in tumors and the rate of apoptotic cells determined by caspase-3 immunostaining and TUNEL were significantly higher in treated rats 20 h after cyclophosphamide treatment as compared with control rats. Conclusion: The effective detection of apoptotic tumor response with 99mTc-annexin V required 20 h after cyclophosphamide treatment in an experimental model. The present results provide an important basis for determining the best timing of annexin V imaging after the start of chemotherapy in a clinical setting.

Original languageEnglish
Pages (from-to)2083-2087
Number of pages5
JournalJournal of Nuclear Medicine
Volume45
Issue number12
StatePublished - 1 Dec 2004
Externally publishedYes

Keywords

  • Apoptosis
  • Cancer chemotherapy
  • Tc-annexin V

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